Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss

Abstract Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. In these diseases, α-synuclein forms dense intracellular aggregates that are disease hallmarks and actively contribute to tissue pathology. Interestingly, many pathological mechani...

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Autores principales:	Andrew D. Sauerbeck, Evan Z. Goldstein, Anthony N. Alfredo, Michael Norenberg, Alexander Marcillo, Dana M. McTigue
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9a2dff3f6e0e49ada4d12e2e9197b909
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spelling	oai:doaj.org-article:9a2dff3f6e0e49ada4d12e2e9197b9092021-12-02T17:51:29ZAlpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss10.1038/s41598-021-91116-32045-2322https://doaj.org/article/9a2dff3f6e0e49ada4d12e2e9197b9092021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91116-3https://doaj.org/toc/2045-2322Abstract Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. In these diseases, α-synuclein forms dense intracellular aggregates that are disease hallmarks and actively contribute to tissue pathology. Interestingly, many pathological mechanisms, including iron accumulation and lipid peroxidation, are shared between classical synucleinopathies such as Alzheimer’s disease, Parkinson’s disease and traumatic spinal cord injury (SCI). However, to date, no studies have determined if α-synuclein accumulation occurs after human SCI. To examine this, cross-sections from injured and non-injured human spinal cords were immunolabeled for α-synuclein. This showed robust α-synuclein accumulation in profiles resembling axons and astrocytes in tissue surrounding the injury, revealing that α-synuclein markedly aggregates in traumatically injured human spinal cords. We also detected significant iron deposition in the injury site, a known catalyst for α-synuclein aggregation. Next a rodent SCI model mimicking the histological features of human SCI revealed aggregates and structurally altered monomers of α-synuclein are present after SCI. To determine if α-synuclein exacerbates SCI pathology, α-synuclein knockout mice were tested. Compared to wild type mice, α-synuclein knockout mice had significantly more spared axons and neurons and lower pro-inflammatory mediators, macrophage accumulation, and iron deposition in the injured spinal cord. Interestingly, locomotor analysis revealed that α-synuclein may be essential for dopamine-mediated hindlimb function after SCI. Collectively, the marked upregulation and long-lasting accumulation of α-synuclein and iron suggests that SCI may fit within the family of synucleinopathies and offer new therapeutic targets for promoting neuron preservation and improving function after spinal trauma.Andrew D. SauerbeckEvan Z. GoldsteinAnthony N. AlfredoMichael NorenbergAlexander MarcilloDana M. McTigueNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrew D. Sauerbeck Evan Z. Goldstein Anthony N. Alfredo Michael Norenberg Alexander Marcillo Dana M. McTigue Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
description	Abstract Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. In these diseases, α-synuclein forms dense intracellular aggregates that are disease hallmarks and actively contribute to tissue pathology. Interestingly, many pathological mechanisms, including iron accumulation and lipid peroxidation, are shared between classical synucleinopathies such as Alzheimer’s disease, Parkinson’s disease and traumatic spinal cord injury (SCI). However, to date, no studies have determined if α-synuclein accumulation occurs after human SCI. To examine this, cross-sections from injured and non-injured human spinal cords were immunolabeled for α-synuclein. This showed robust α-synuclein accumulation in profiles resembling axons and astrocytes in tissue surrounding the injury, revealing that α-synuclein markedly aggregates in traumatically injured human spinal cords. We also detected significant iron deposition in the injury site, a known catalyst for α-synuclein aggregation. Next a rodent SCI model mimicking the histological features of human SCI revealed aggregates and structurally altered monomers of α-synuclein are present after SCI. To determine if α-synuclein exacerbates SCI pathology, α-synuclein knockout mice were tested. Compared to wild type mice, α-synuclein knockout mice had significantly more spared axons and neurons and lower pro-inflammatory mediators, macrophage accumulation, and iron deposition in the injured spinal cord. Interestingly, locomotor analysis revealed that α-synuclein may be essential for dopamine-mediated hindlimb function after SCI. Collectively, the marked upregulation and long-lasting accumulation of α-synuclein and iron suggests that SCI may fit within the family of synucleinopathies and offer new therapeutic targets for promoting neuron preservation and improving function after spinal trauma.
format	article
author	Andrew D. Sauerbeck Evan Z. Goldstein Anthony N. Alfredo Michael Norenberg Alexander Marcillo Dana M. McTigue
author_facet	Andrew D. Sauerbeck Evan Z. Goldstein Anthony N. Alfredo Michael Norenberg Alexander Marcillo Dana M. McTigue
author_sort	Andrew D. Sauerbeck
title	Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
title_short	Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
title_full	Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
title_fullStr	Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
title_full_unstemmed	Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
title_sort	alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9a2dff3f6e0e49ada4d12e2e9197b909
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Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss

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